Clinical and neurochemical studies have provided compelling evidence that cortical cholinergic pathways are consistently and severely affected in Alzheimer's type cementia (AD). We have demonstrated in the rat that the primary source of cortical cholinergic innervation is the nucleus basalis (nBM) and that these neurons degenerate in patients dying with AD. We shall use the rat to define better the neuroanatomy, synaptic chemistry, the behavioral role and pharmacology of the basal forebrain cholinergic projections innervating the neocortex and hippocampal formation. The following studies will be undertaken: 1) Through the combined application of selective excitotoxin lesions, neurochemical analysis and retograde histologic methods, we shall define the topographic organization of the magnocellular cholinergic projections to cerebral cortex. 2) The role of cortical cholinergic afferents and intrinsic neurons in the regulation of cortical muscarinic receptors will be examined with a combination of pharmacologic and lesion techniques. 3) The contribution of cortical intrinsic neurons to acetylcholine function in cortex and their response to loss of the nBM input will be examined. 4) The effects of the nBM lesion on the pre- and post-synaptic components of the cortical noradrenergic function develops after cortical cholinergic dennervation. 5) The effects of excitotoxin lesions in subareas of the basal forebrain cholinergic nuclei on global psychological processes will be assessed. A detailed examination of memory processes, with particular emphasis on working memory will be performed; and the types of memory processing, which are impaired or sprayed, will be correlated with the neurochemical and histologic aspects of the lesions. 6) As the nBM excitotoxin lesion partially mimics the pathology of AD, we shall examine the effects of cholinomimetic drugs of potential therapeutic benefit for AD on the synaptic chemistry and behavior of lesioned rats. These basic studies in the rat may clarify the role of the nBM cholinergic deficit in the pathophysiology of AD.